CELL CYCLE-INDEPENDENT INDUCTION OF APOPTOSIS BY THE ANTITUMOR DRUG FLAVOPIRIDOL IN ENDOTHELIAL-CELLS

The anti-tumor drug Flavopiridol is a potent inhibitor of cyclin-depen dent kinases (cdks). As a consequence, Flavopiridol-treated cells arre st in both G(1) and G(2), but Flavopiridol has also been shown to be c ytotoxic for some turner cell lines. The underlying molecular events a re, however, unclear. We now show that Flavopiridol induces apoptosis in human umbilical vein endothelial cells (HUVECs), as judged by the o ccurrence of classical apoptotic markers, including chromatin condensa tion, internucleosomal cleavage, DNA fragmentation (TUNEL assay), anne xin V binding and poly(ADP-ribose) polymerase (PARP)-cleavage. Such in duction of apoptosis occurs with equal efficiency in both proliferatin g and G(0)/G(1)-arrested cells. Because growth-arrested HUVECs lack cd k2 activity and contain high levels of the cdk inhibitor p27, our obse rvations suggest that cell cycle regulated cdks may not be the only cr itical target for Flavopiridol-induced apoptosis. Surprisingly, A549 l ung carcinoma cells were clearly dependent on cell proliferation for t he induction of cell death, pointing to cell type-related differences in the mechanism of Flavopiridol action. (C) 1998 Wiley-Liss, Inc.